First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Initial Experience With Propranolol Treatment of Lymphatic Anomalies: A Case Series.

Lymphatic malformations (LMs) are congenital lymphatic lesions that impose significant and costly morbidities on affected patients. Treatment options are limited due to incomplete understanding of LM pathobiology. Expression of an activated ß2-adrenergic receptor has been described in LM tissue, suggesting that this pathway may contribute to the clinical manifestations of LM. We hypothesized that propranolol, a ß-adrenergic receptor antagonist, might improve symptoms of patients with LMs and lymphatic anomalies. A retrospective chart review of patients treated with propranolol as an adjunct therapy was conducted; analyses included demographic characteristics, clinical features, and response to propranolol. Three patients with cystic and noncystic LMs displayed clinical improvement at a minimum dose of 0.7 mg/kg/d, whereas symptomatic relapses were observed when propranolol doses dropped below this threshold. Two patients with Klippel-Trenaunay syndrome demonstrated partial clinical responses with reduced edema. The fetus of a mother treated with propranolol from a gestational age of 35 weeks through delivery displayed arrested growth of a cervicofacial LM. Our retrospective review suggests that propranolol improved symptoms in a subset of patients with lymphatic anomalies. Propranolol treatment may also limit the growth of congenital LMs in utero.

Diagnosis of a rare fetal haemoglobinopathy in the age of next-generation sequencing.

Neonatal cyanosis resulting from a fetal methaemoglobin variant is rare. Most such variants are only described in a few published case reports. We present the case of a newborn with unexplained persistent cyanosis, ultimately determined to have a γ-chain mutation causing Hb FM-Fort Ripley. This neonatal haemoglobinopathy can be challenging to diagnose, as significant oxygen desaturation may result from barely detectable levels of the mutant haemoglobin and co-oximetry studies may show a falsely normal methaemoglobin level. Our analysis of the infant's haemoglobin included high-performance liquid chromatography, cellulose acetate electrophoresis and citrate agar electrophoresis, which showed trace amounts of a suspected variant. Ultimately, the diagnosis was made through a novel application of next-generation sequencing (NGS). NGS-based diagnostic approaches are becoming increasingly available to clinicians, and our case provides a framework and evidence for the utilisation of such testing paradigms in the diagnosis of a rare cause of neonatal cyanosis.

A pilot randomized trial evaluating low-level laser therapy as an alternative treatment to manual lymphatic drainage for breast cancer-related lymphedema.

PURPOSE/OBJECTIVES: To examine the impact of advanced practice nurse (APN)-administered low-level laser therapy (LLLT) as both a stand-alone and complementary treatment for arm volume, symptoms, and quality of life (QOL) in women with breast cancer-related lymphedema. DESIGN: A three-group, pilot, randomized clinical trial. SETTING: A private rehabilitation practice in the southeastern United States. SAMPLE: 46 breast cancer survivors with treatment-related lymphedema. METHODS: Patients were screened for eligibility and then randomized to either manual lymphatic drainage (MLD) for 40 minutes, LLLT for 20 minutes, or 20 minutes of MLD followed by 20 minutes of LLLT. Compression bandaging was applied after each treatment. Data were collected pretreatment, daily, weekly, and at the end of treatment. MAIN RESEARCH VARIABLES: Independent variables consisted of three types of APN-administered lymphedema treatment. Outcome variables included limb volume, extracellular fluid, psychological and physical symptoms, and QOL. FINDINGS: No statistically significant between-group differences were found in volume reduction; however, all groups had clinically and statistically significant reduction in volume. No group differences were noted in psychological and physical symptoms or QOL; however, treatment-related improvements were noted in symptom burden within all groups. Skin improvement was noted in each group that received LLLT. CONCLUSIONS: LLLT with bandaging may offer a time-saving therapeutic option to conventional MLD. Alternatively, compression bandaging alone could account for the demonstrated volume reduction. IMPLICATIONS FOR NURSING: APNs can effectively treat lymphedema. APNs in private healthcare practices can serve as valuable research collaborators. KNOWLEDGE TRANSLATION: Lasers may provide effective, less burdensome treatment for lymphedema. APNs with lymphedema certification can effectively treat this patient population with the use of LLLT. In addition, bioelectrical impedance and tape measurements can be used to assess lymphedema.